It is estimated that 170 million people worldwide are infected with hepatitis C virus (HCV). HCV infection routinely results in chronic hepatitis that may progress over time to further liver disease, including cirrhosis and hepatocellular carcinoma. Chronic HCV infection is one of the leading risk factors associated with endstage liver disease and subsequent liver transplantation. Overall, our understanding of the viral-host interactions in vivo is severely limited. The inability to produce live virus in culture, combined with the lack of a reliable small animal model, have impeded progress in determining exactly how HCV contributes to liver disease pathology. Understanding where HCV is located, and in what cell types infection occurs, is critical to deciphering many unknown aspects of the HCV life cycle; however detecting sites of replication remains a major challenge. The objective of this proposal is to provide unequivocal in situ data regarding HCV site of replication, determine if an in vivo association exists with proliferating cell populations, and analyze viral effects on cellular gene expression, in order to provide greater insight into the mechanisms of pathogenesis in HCV infection.